The peroxisome proliferator-activated receptors (PPARs) are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily. The PPARs were originally identified as orphan receptors, without known ligands, but were named for their ability to mediate the pleiotropic effects of fatty acid peroxisome proliferators. At least three mammalian PPARs have been isolated: PPARγ, PPARα and PPARδ (PPARβ, NUC1). These receptors function as ligand-regulated transcription factors that control the expression of target genes by binding to their responsive DNA sequence as heterodimers with RXR. The target genes encode enzymes involved in lipid metabolism and differentiation of adipocytes. Accordingly, the discovery of transcription factors involved in controlling lipid metabolism has provided insight into regulation of energy homeostasis in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes and dyslipidemia.
PPARγ is one member of the nuclear receptor superfamily of ligand-activated transcription factors and has been shown to be expressed in an adipose tissue-specific manner. Its expression is induced early during the course of differentiation of several preadipocyte cell lines. Additional research has now demonstrated that PPARγ plays a pivotal role in the adipogenic signaling cascade. PPARγ also regulates the ob/leptin gene which is involved in regulating energy homeostasis, and adipocyte differentiation which has been shown to be a critical step to be targeted for anti-obesity and diabetic conditions.
In an effort to understand the role of PPARγ in adipocyte differentiation, several investigators have focused on the identification of PPARγ activators. One class of compounds, the thiazolidinediones, which were known to have adipogenic effects on preadipocyte and mesenchymal stem cells in vitro, and antidiabetic effects in animal models of non-insulin-dependent diabetes mellitus (NIDDM) were also demonstrated to be PPARγ-selective ligands. More recently, compounds that selectively activate murine PPARγ were shown to possess in vivo antidiabetic activity in mice.
Despite the advances made with the thiazolidinedione class of antidiabetes agents, unacceptable side effects have limited their clinical use. Accordingly, there remains a need for potent, selective activators of PPARγ which will be useful for the treatment of NIDDM and other disorders related to lipid metabolism and energy homeostasis. Still further, compounds that block PPARγ activity would be useful for interfering with the maturation of preadipocytes into adipocytes and thus would be useful for the treatment of obesity and related disorders associated with undesirable adipocyte maturation.
Evidence suggests that PPARδ controls the peroxisomal beta-oxidation pathway of fatty acids. Activators of PPARδ have been shown to promote reverse cholesterol transport, which can raise HDL cholesterol levels. See, Oliver et al. (2001) Proc. Natl. Acad. Sci. USA 98(9):5306-5311. It has also been shown that PPARδ activators inhibit the formation of the inflammatory mediator's inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF). See, U.S. Pat. No. 6,869,975; International Publication No. WO 02/28434 to Buchan et al. Moreover, it has been shown that PPARδ, unlike PPARγ or PPARα, represents a β-catenin/Tcf-4 target with particular importance for chemoprevention (He et al. (1999) Cell 99:335-345).
The identification of compounds which modulate PPARδ provides an opportunity to probe PPARδ mediated processes and discover new therapeutic agents for conditions and diseases associated therewith, such as cardiovascular disease, atherosclerosis, diabetes, obesity, syndrome X and malignant diseases.
The present invention provides compounds that are useful as activators as well as antagonists of PPARγ or PPARδ activity, compositions containing them and methods for their use.